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Cell Mol Gastroenterol Hepatol. 2019 Feb 1. pii: S2352-345X(19)30005-0. doi: 10.1016/j.jcmgh.2019.01.004. [Epub ahead of print]

Modulation of Gut Microbiota Composition by Serotonin Signaling Influences Intestinal Immune Response and Susceptibility to Colitis.

Author information

1
Farncombe Family Digestive Health Research Institute; Department of Pathology and Molecular Medicine.
2
Farncombe Family Digestive Health Research Institute; Department of Pathology and Molecular Medicine; Department of Biochemistry and Biomedical Sciences.
3
University of Manitoba, Winnipeg, Manitoba, Canada.
4
Farncombe Family Digestive Health Research Institute; Department of Biochemistry and Biomedical Sciences.
5
Farncombe Family Digestive Health Research Institute; Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
6
Farncombe Family Digestive Health Research Institute; Department of Pathology and Molecular Medicine. Electronic address: khanwal@mcmaster.ca.

Abstract

BACKGROUND & AIMS:

Serotonin (5-hydroxytryptamine; 5-HT) is synthesized mainly within enterochromaffin (EC) cells in the gut, and tryptophan hydroxylase 1 (Tph1) is the rate-limiting enzyme for 5-HT synthesis in EC cells. Accumulating evidence suggest the importance of gut microbiota in intestinal inflammation. Considering the close proximity of EC cells and the microbes, we investigate the influence of gut-derived 5-HT on the microbiota and the susceptibility to colitis.

METHODS:

Gut microbiota of Tph1-/- and Tph1+/- mice were investigated by deep sequencing. Direct influence of 5-HT on bacteria was assessed utilizing in vitro system of isolated commensals. The indirect influence of 5-HT on microbiota was assessed by measuring antimicrobial peptides, specifically β-defensins, in the colon of mice and HT-29 colonic epithelial cells. The impact of gut microbiota on the development of dextran sulfate sodium (DSS)-induced colitis was assessed by transferring gut microbiota from Tph1-/- mice to Tph1+/- littermates and vice-versa, as well as in germ-free (GF) mice.

RESULTS:

A significant difference in microbial composition between Tph1-/- and Tph1+/- littermates was observed. 5-HT directly stimulated and inhibited the growth of commensal bacteria in vitro, exhibiting a concentration-dependent and species-specific effect. 5-HT also inhibited β-defensin production by HT-29 cells. Microbial transfer from Tph1-/- to Tph1+/- littermates and vice versa altered colitis severity with microbiota from Tph1-/- mice mediating the protective effects. Furthermore, GF mice colonized with microbiota from Tph1-/- mice exhibited less severe DSS-induced colitis.

CONCLUSIONS:

These findings demonstrate a novel role of gut-derived 5-HT in shaping gut microbiota composition in relation to susceptibility to colitis, identifying 5-HT-microbiota axis as a potential new therapeutic target in intestinal inflammatory disorders.

KEYWORDS:

5-Hydroxytryptamine (5-HT); Colitis; Microbiota; Tph1; β-defensins

PMID:
30716420
DOI:
10.1016/j.jcmgh.2019.01.004
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